Tremendous progress has been made in recent years in the design and synthesis of peptides and peptidomimetics with high affinity and high selectivity for the different types (mu, delta, kappa) of opioid peptides. However, the clinical development of these synthetic opioid peptides and peptidomimetics has been seriously limited by their poor biopharmaceutical properties (e.g. low permeation through the intestinal mucosa and the blood-brain barrier). With support from this NIDA grant, we have designed and synthesized esterase-sensitive cyclic prodrugs of a model opioid peptide (DADLE) that exhibit physicochemical properties (hydrophobicity, low hydrogen bonding potential, no charge) favorable for high transcellular permeation. However, these cyclic prodrugs were shown to exhibit substrate activity for efflux transporters (e.g. MDR1, MRP2) which restrict their permeation across the intestinal mucosa and the blood-brain barrier. If these efflux transporters in the blood-brain barrier are inhibited, the "intrinsic" permeability coefficients (Papp) of these cyclic prodrugs are 100-300 fold higher than the Papp value for DADLE itself. Based on these exciting observations, we plan during the next grant period to focus on the optimization of the bio-pharmaceutical properties of the cyclic prodrugs, including: (i) minimizing their substrate activity for the efflux transporters that limit their intestinal mucosal and blood-brain barrier permeation while maintaining their good "intrinsic" permeation characteristics; (ii) optimizing their conversion to DADLE in the target tissue (brain) and minimizing their conversien in the blood compartment; and (iii) minimizing their clearance by the liver so as to increase their residency time in the blood, thus maximizing the opportunity for the prodrug to partition across the blood-brain barrier. The results of the studies proposed in this renewal application should allow for the design of second generation cyclic prodrugs of opioid peptides that will afford optimal pharmacological effects after i.v. or oral administration.